Molecular dissection of abnormal regulation of cancer gene expression has revealed many potential targets for cancer therapy. Those targets include the components of normal, as well as abnormal transcription machinery. Proteins involved in regulation of transcription in cancer will attain high priority due to the convergence of many signal transduction pathways at the transcriptional level. New molecular therapies directed to transcriptional targets, including siRNA technology have significant advantages over traditional therapies due to a precision of their interference with target gene expression. While rapid progress in molecular genetics and medicinal chemistry delivers new +attenuators;of gene expression, there is a critical need in developing technologies that enable early and non-invasive assessment of cancer response to these therapies. In particular, enabling imaging technologies that report directly on gene transcription in cancer cells are critically important for both cancer phenotyping and staging, as well as for evaluating new therapies. Optical imaging in the near-infrared range of fluorescence combined with the use of enzyme-specific self- quenched probes has emerged as novel technology of live cancer cell screening. We previously devised a family of fluorescent probes based on synthetic biocompatible carriers of fluorochromes that report on hydrolytic activity in tumor-bearing animals. Recently, we developed new chemistry for generating asymmetrical as well symmetrical oligonucleotide molecular reporter probes (ODMR) designed to sense interactions with pleiotropic and evolutionally conserved components of transcriptional factor nuclear factor NFkappaB (NF-?B). NF-?B plays one of the key roles in tumor progression by regulating expression of cell adhesion, antiapoptotic and cytokine responsive genes in cancer and stromal cells in tumors. We recently tested novel synthetic approaches for introducing hydrophilic, non-interfering linkers into ?B-box sequences for covalent binding of fluorochromes to these probes to any internucleoside phosphate. We propose to develop ODMR technology that will be essential for further advancement of in vivo imaging of cancer-related target transcription activators.